Colorectal cancer is the third most common cancer in both men and women in the United States. The highest risk groups for developing colon cancer are those with a genetic predisposition and those with inflammatory bowel disease. For individuals with inflammatory bowel disease, the risk correlates with extent and duration of inflammation affecting the colon and can be increased 5- to 15-fold compared to normal individuals. Mouse models of inflammation-related colon cancer have demonstrated that intestinal bacteria and the host immune system can regulate intestinal inflammation and carcinogenesis. In particular, members of the Nod-like receptor family have emerged as important players in the development of intestinal inflammation and cancer. NLRs are intracellular pattern-recognition receptors that are involved in the sensing of both pathogenic and commensal bacteria within the gut. We have recently identified a relatively unknown member of the NLR family, Nlrp6, which is important for intestinal homeostasis and tumor suppression during chronic injury and inflammation within the colon. However, the mechanism by which Nlrp6 reduces tumor development and inflammation in the colon remains to be elucidated. We hypothesize that Nlrp6 modulates susceptibility to intestinal inflammation and tumorigenesis by regulating the composition of the gut microbiota and the production of IL-18. Our specific aims are: (1) to determine the importance of Nlrp6 in regulating the gut microbiome to increase susceptibility to colonic inflammation and cancer, (2) to identify the cell type that Nlrp6 functions in to suppress tumorigenesis, and 3) to understand the role of IL-18 in Nlrp6-mediated tumor suppression. The long-term goal of these studies is to increase our understanding of how interactions between NLRs and the gut microbiota regulate colon carcinogenesis, which may lead to novel chemopreventive strategies for colon cancer involving the manipulation of the intestinal bacteria and/or modulation of NLR signaling pathways.